7kpm

From Proteopedia

(Difference between revisions)

Revision as of 15:29, 18 October 2023

Crystal structure of hEphB1 bound with ADP

Structural highlights

7kpm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.608Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

EPHB1_HUMAN Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. Beside its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.,Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). pii: 2016265118. doi:, 10.1073/pnas.2016265118. PMID:33627480^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stein E, Huynh-Do U, Lane AA, Cerretti DP, Daniel TO. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J Biol Chem. 1998 Jan 16;273(3):1303-8. PMID:9430661
↑ Stein E, Lane AA, Cerretti DP, Schoecklmann HO, Schroff AD, Van Etten RL, Daniel TO. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev. 1998 Mar 1;12(5):667-78. PMID:9499402
↑ Han DC, Shen TL, Miao H, Wang B, Guan JL. EphB1 associates with Grb7 and regulates cell migration. J Biol Chem. 2002 Nov 22;277(47):45655-61. Epub 2002 Sep 9. PMID:12223469 doi:10.1074/jbc.M203165200
↑ Vindis C, Cerretti DP, Daniel TO, Huynh-Do U. EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol. 2003 Aug 18;162(4):661-71. PMID:12925710 doi:http://dx.doi.org/10.1083/jcb.200302073
↑ Fasen K, Cerretti DP, Huynh-Do U. Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway. Traffic. 2008 Feb;9(2):251-66. Epub 2007 Dec 19. PMID:18034775 doi:http://dx.doi.org/10.1111/j.1600-0854.2007.00679.x
↑ Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES. Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). pii: 2016265118. doi:, 10.1073/pnas.2016265118. PMID:33627480 doi:http://dx.doi.org/10.1073/pnas.2016265118

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7kpm"

Categories: Homo sapiens | Large Structures | Ahmed M | Sadek H | Wang P

@@ Line 1: / Line 1: @@
 ==Crystal structure of hEphB1 bound with ADP==
-<StructureSection load='7kpm' size='340' side='right'caption='[[7kpm]]' scene=''>
+<StructureSection load='7kpm' size='340' side='right'caption='[[7kpm]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KPM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KPM FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7kpm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KPM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KPM FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kpm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kpm OCA], [https://pdbe.org/7kpm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kpm RCSB], [https://www.ebi.ac.uk/pdbsum/7kpm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kpm ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.608&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kpm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kpm OCA], [https://pdbe.org/7kpm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kpm RCSB], [https://www.ebi.ac.uk/pdbsum/7kpm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kpm ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/EPHB1_HUMAN EPHB1_HUMAN] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. Beside its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively.<ref>PMID:9430661</ref> <ref>PMID:9499402</ref> <ref>PMID:12223469</ref> <ref>PMID:12925710</ref> <ref>PMID:18034775</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.
+Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.,Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). pii: 2016265118. doi:, 10.1073/pnas.2016265118. PMID:33627480<ref>PMID:33627480</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7kpm" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Ahmed M]]
 [[Category: Sadek H]]
 [[Category: Wang P]]

7kpm

From Proteopedia

Revision as of 15:29, 18 October 2023

Crystal structure of hEphB1 bound with ADP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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